Omeprazole is a proton pump inhibitor, i.e. effective in inhibiting gastric acid secretion, and is useful as an antiulcer agent In a more general sense, omeprazole may be used for treatment of gastric-acid related diseases in mammals and especially in man.
The compound 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole, having the generic name omeprazole, as well as therapeutically acceptable is salts thereof, are described in EP 5129. Ohishi et al., Acta Cryst (1989), C45, 1921-1923, describe single crystal X-ray data and the derived molecular structure of one crystal form of omeprazole. A second crystal form of omeprazole is disclosed in WO 99/08500. These crystal forms are referred to herein as omeprazole forms B and A, respectively.
WO 01/14367 discloses isomers of omeprazole having the methoxy group on the benzimidazole ring at either the 6- or the 5-position. These two forms are referred to herein as “6-methoxy” and “5-methoxy”, respectively or alternatively referred to as “6-isomer” and “5-isomer”, respectively. WO 01/13919 discloses a method based on FT-Raman spectroscopy to determine the ratio of the 6- and 5-isomer of omeprazole present in a mixture thereof. The method of WO 01/13919 is based on the assumption that the 5-isomer and the 6-isomer have the same Raman scattering efficiency.
Isomers are chemical compounds that have the same molecular formulae but different molecular structures or different arrangements of atoms in space (see A Dictionary of Science, Oxford University Press, 1999). In structural isomerism the molecules have different molecular structures, i.e. they may be different types of compound or they may simply differ in the position of the functional groups in the molecule. Structural isomers generally have different physical and chemical properties. Tautomerism is a type of isomerism in which the two isomers (tautomers) are in equilibrium. The most wellknown tautomerism is the keto-enol tautomerism. In the keto-enol tautomerism one compound containing a —CH2—CO— group (the keto form of the molecule) is in equilibrium with one containing the —CH═C(OH)— group (the enol). The keto-enol tautomerism occurs by migration of a hydrogen atom between a carbon atom and the oxygen on an adjacent carbon. Tautomers can therefore be said to be isomers that are rapidly interconverted in solution phase. The keto-enol tautomerism is schematically shown in Scheme 1 below.
Benzimidazole is also wellknown to exhibit tautomerism, see e.g. Lee and Jeoung, “Synthesis and Tautomerism of 2-Aryl- and 2-heteroaryl Derivatives of Benzimidazole”, J. Heterocyclic Chem., 33, 1711 (1996); and Jacoby et al, “A comparison of intermolecular vibrations and tautomerism in benzimidazole, benzotriazole and their binary water clusters”, Appl. Phys. B71, 643-639, (2000), and its 13C-NMR spectrum shows only four peaks in spite of seven carbon atoms being present. Structure, atom numbering, and tautomerism of benzimidazole are shown in Scheme 2 below.

In the benzimidazole case the tautomerism occurs by migration of a hydrogen atom between the two nitrogen atoms. However, the 1H and “3H” tautomers are identical to each other unless the benzimidazole is assymetrically substituted. This phenomenon is discussed in U.S. Pat. No. 5,039,806 which relates to 2-pyridinyl methylsulfinyl benzimidazole compounds structurally related to omeprazole.

Omeprazole with its methoxy group in the 5 position of the benzimidazole is monosubstituted and is thus assymetrically substituted. Consequently the 1H and “3H” tautomers are not identical. The IUPAC-nomenclature of these two isomers are 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole and 6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole, referred to herein as the 5-methoxy and 6-metoxy isomers, as is indicated in Scheme 3 above.
The 5-isomer of omeprazole is thus a tautomer to the 6-isomer of omeprazole.
As discussed above tautomers are isomers that are rapidly interconverted in solution. This interconversion is very rapid but can be slowed down by decreasing the temperature. Two tautomers usually have different energy in solution and one tautomer (or isomer) is therefore of lower energy and more stable.
Solid phase is different from solution phase and the interconversion of tautomers (isomers) is usually non-existing in the solid phase. However, two tautomers may still be of different energy and one tautomer may therefore be more stable than the other also in the solid state.
Crystallisation is a process to precipitate a solid material from a solution thereof by allowing the concentration of the material to be above the saturation point so that the excess of the material is separated as crystals.
Polymorphism is the ability of elements or compounds to exist in more than one crystal is form, with each having the same chemical composition but different physical properties due to differences in the arrangement of atoms (A Dictionary of Earth Sciences, Oxford University Press 1999). Examples of polymorphs are graphite and diamond (both carbon); alpha and beta quartz (both SiO2); and calcite (hexagonal) and aragonite (orthorhombic), both forms of CaCO3. The external form of the crystal is referred to as the crystal habit. The atoms, ions, or molecules forming the crystal have a regular arrangement and this is the crystal structure (A Dictionary of Science, Oxford University Press, 1999).
Polymorphs differ in their crystal structures and they often have different properties, like rate of dissolution, stability and melting point. Different polymorphs can be characterized by e.g. X-ray Powder Diffraction (XRPD), differential scanning calorimetry (DSC), microscopy or spectroscopy. XRPD measurements show mainly variation in the unit cell parameters, while Raman spectroscopy mainly shows differences in molecular conformation. It is common in polymorphs that both the unit cell and the molecular conformation vary.
Omeprazole exists in two different crystal forms (polymorphs). The first is disclosed by Ohishi et al., Acta Cryst (1989), C45, 1921-1923, and is referred to as omeprazole form B. The second polymorph is disclosed in WO 99/08500 and is referred to as omeprazole form A. Omeprazole form A is in the solid state more stable than omeprazole form B, both thermodynamically and chemically. Omeprazole form B can be converted into form A by recrystallisation.
Omeprazole form A consists of the 6-isomer and omeprazole form B consists of a mixture of the 6- and 5-isomers, more specifically it consists of about 86% 6-isomer and about 14% 5-isomer (corrected values).
The different isomers and crystal forms of omeprazole can thus either be explained as a difference in the distribution of 5- and 6-methoxy isomer, or as a difference in the distribution between crystal forms A and B.
The amount of form A and form B is related to the amount of 5-isomer and 6-isomer, pure form A having no 5-isomer, pure form B having about 20% 5-isomer, and about 80% 6-isomer (FT-Raman values, not corrected for solid-state NMR data). The corresponding corrected values for form B is as discussed above about 86% 6-isomer and about 14% 5-isomer.
In the Raman spectrum of omeprazole, a peak is observed at 1355 cm−1. If the 5-methoxy isomer is present, an additional Raman peak is observed at 1364 cm−1 that is absent for the spectrum of pure 6-methoxy isomer. If the intensity of the two peaks is measured then the relative amount of 5- and 6-methoxy isomer present in a mixture thereof can be determined from the peak ratio.
However, it has now surprisingly been found that the two isomers of omeprazole have different Raman scattering efficiency and this has to be taken into account when calculating the amount of 5- and 6-isomer of omeprazole. If this is not properly done the wrong ratio of 5- and 6-isomer of omeprazole present in a mixture thereof will be calculated. This is of importance since mixtures, wherein the isomers have different ratios, have different solid state stability.
The FT-Raman spectrum is specific for omeprazole and differs from that of even closely related compounds, eg omeprazole salts. The band pair at 1355/1364 cm−1 is characteristic for the 5- and 6-isomers of omeprazole.